Acquired drug resistance is a serious problem for the treatment of metastatic melanoma. Current treatments have low specificity, high toxicity toward healthy cells, and induce drug-resistance. We have designed cyclic peptides inspired on spider and horseshoe crab peptides with a Beta-hairpin structure that selectively target and kill melanoma cells, including those harbouring BRAF V600E mutation. These peptides are resistant to proteases, can cross cell membranes, and are amenable to structural modifications. We have identified peptide analogues able to kill drug-sensitive and drug-resistant metastatic melanoma cells that have developed resistance to Dabrafenib, a small molecule drug used to treat patients with metastatic melanoma with BRAF V600E mutation. In addition, metastatic melanoma cells did not develop tolerance to tested peptides. Thus, these host defense peptides are well suited as templates to design therapeutic leads to target drug-resistant metastatic melanoma cells and/or as co-treatment with small molecule drugs. I will present results on the activity and mechanism of these anti-melanoma peptides and on lipidomic studies of melanoma cell membranes while acquiring drug-resistance.